Cardiovascular disease is the number one cause of death in postmenopausal women. Postmenopausal estrogen replacement therapy is associated with a lower incidence of cardiovascular disease in women, especially in those with established coronary artery disease. The strength of the apparent effect of estrogen in epidemiologic studies suggest that estrogen plays a fundamental role in the maintenance of vascular health - one that if better understood could significantly advance our understanding of the pathogenesis and prevention of atherosclerosis. Recent animal data suggest that the current practice of adding low dose progesterone to prevent endometrial hyperplasia may inhibit the beneficial effects of estrogen on coronary arteries. Before committing millions of postmenopausal women to long-term estrogen use for prevention of coronary artery disease, it is mandatory to demonstrate that it does indeed protect against coronary atherosclerosis, to determine the impact of co-treatment with progestin, and to understand the mechanisms through which estrogen may exert its cardioprotective effects. If estrogen is causally related to a reduction in coronary artery disease, the mechanisms could include 1.) an inhibition of atherosclerotic plaque accumulation along with its associated risk for acute ulceration and thrombosis, or 2.) protection against atherosclerotic impairment of endothelial function, or a complex interaction of these two mechanisms. These mechanisms may be mediated through estrogen associated changes in plasma lipids, blood pressure regulation, carbohydrate metabolism, plasma antioxidant activity, or hemostatic factors. The availability of established techniques including quantitative coronary angiography and intracoronary acetylcholine infusions to measure both anatomic and functional coronary disease, coupled with the detailed measurement of many potential mediators provide a rich opportunity to answer many of the pressing questions concerning estrogen replacement therapy and coronary disease. The proposed Estrogen Replacement and Atherosclerosis (ERA) Trial is designed to determine if estrogen replacement therapy with or without low dose progesterone will slow the progression or induce regression of the anatomic and functional sequelae of atherosclerosis on coronary arteries in 306 postmenopausal women with established coronary atherosclerosis. There is a high likelihood that the proposed trial will significantly advance our understanding of the effects of estrogen on coronary artery disease in postmenopausal women and provide new directions for basic and clinical research concerning the prevention of atherosclerosis.